Occlusive cardiovascular diseases, including hypertension, atherosclerosis, neointimal hyperplasia (NIHA), and restenosis, heave been reported to be closely coupled with the proliferation and migration of coronary artery smooth muscle cells (CSM). Current treatments for restenosis deal with the temporal pathological processes which involve blood coagulation, inflammation, proliferation/migration of smooth muscle cells, and endothelialization. Drug-eluting stents (DESs), composed of bare metal stents, polymer coatings and antiproliferative drugs, are used clinically to treat severe coronary atherosclerosis and have been shown to reduce in-stent restenosis. Current drugs used in DESs in the clinic generally act by non-specifically and/or non-selectively blocking all cell cycling and cell division (e.g., paclitaxel, rapamycin) in all areas near or accessible to the drugs in the stent. It has been reported that because of the lack of specificity and/or selectivity in the action of the drug on non-target cells and cell types, a delay in the recovery of a denuded endothelial layer is observed. Such delay may lead to increased thrombosis.
It has been discovered herein that stents that include adenosine receptor modulators are useful in treating vascular injury and in preventing and/or slowing the progression of restenosis. In one illustrative embodiment, devices are described herein that may be implanted in the vasculature, such as in blood vessels, and in particular coronary blood vessels. In one aspect, the devices include a stent that has a coating, where the coating includes one or more adenosine receptor modulators. In another aspect, the coating also includes a polymer or polymeric matrix. In another embodiment, the modulators are incorporated into the polymer or polymeric matrix, which is adhered to the stent. It is appreciated that the polymers and polymeric matrices described herein are desirably biocompatible.
In another embodiment at least one adenosine receptor modulator is an adenosine A1 receptor antagonist. In another embodiment, at least one adenosine receptor modulator is an adenosine A2 receptor agonist, such as an adenosine A2B receptor agonist. In another embodiment, at least one adenosine receptor modulator is an adenosine A2 receptor agonist, such as an adenosine A2A receptor agonist. In another embodiment, at least one adenosine receptor modulator is an adenosine A3 receptor modulator.
In another embodiment, the coating includes two or more adenosine receptor modulators. In another embodiment, the coating includes a combination of at least one adenosine receptor antagonist, such as an A1 receptor antagonist, and at least one adenosine receptor agonist, such as an A2 receptor agonist, for example an adenosine A2B receptor agonist and/or an adenosine A2A receptor agonist. It is to be understood that any and all combinations of various adenosine receptor modulators are described herein.
In another embodiment, methods for treating vascular disease or injury, such as inhibiting restenosis, are described herein, where the methods include implanting a stent described herein into a blood vessel. In one aspect, the adenosine receptor modulator is releasable from the stent in a therapeutically effective amount to treat a vascular disease or injury, such as a therapeutically effective amount to inhibit restenosis.
In another embodiment, processes for manufacturing stents are also described. The processes include applying a mixture of one or more adenosine receptor modulators and a polymer or polymer matrix to a metal stent.